Intravenous and oral antiplatelet/antithrombotic efficacy and specificity of XR300, a novel nonpeptide platelet GPIIb/IIIa antagonist

Currently used antiplatelet drugs including aspirin, ticlopidine, and others are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus our study was undertaken to define the antiplatelet efficacy, specificity, and the intravenous and oral antiplatelet/antithrombotic effects of a nonpeptide glycoprotein αIIbβ3 integrin (GPIIb/IIIa) antagonist XR300, an ethyl ester prodrug of XR299. XR300, on its conversion to the active form XR299, inhibited human platelet aggregation induced by 100 μM adenosine diphosphate (ADP) with a median inhibitory concentration (IC 50 ) of 0.09 μM. Similarly, XR299 inhibited 125 I-fibrinogen binding to human gel-purified platelets (IC 50 , 0.01 μM) regardless of the agonist used. In purified human GPIIb/IIIa, XR299 demonstrated a competitive high-affinity binding with an IC 50 of 1.2 nM. XR299 demonstrated a high degree of specificity for platelet GPIIb/IIIa (α IIb β 3 ) as compared with other integrins including α v β 3 , α V β 5 , and α 4 β 1 , where IC 50 values were >10 μM. XR300 administered to mongrel dogs either intravenously (0.5-1.0 mg/kg, i.v.) or orally at 1.0-2.0 mg/kg, demonstrated maximal antiplatelet effects with rapid onset and extended duration. XR300 demonstrated maximal antithrombotic efficacy in preventing the incidence of occlusive thrombosis or cyclic flow reduction (CFR) in the carotid or femoral artery thrombosis models induced either electrolytically or by mechanical injury along with stenosis. In conclusion, XR300 is a novel intravenous and oral antiplatelet/antithrombotic agent with high affinity and specificity for platelet GPIIb/IIIa receptors.